Analyte Sensor Calibration Management

ABSTRACT

Methods and devices to detect analyte in body fluid are provided. Embodiments include positioning an analyte sensor in fluid contact with an analyte, detecting an attenuation in a signal from an analyte sensor after positioning during a predetermined time period, categorizing the detected attenuation in the analyte sensor signal based, at least in part, on one or more characteristics of the signal, performing signal processing to generate a reportable data associated with the detected analyte sensor signal during the predetermined time period, managing if and when to request additional reference signal measurements, and managing if and when to temporarily not display results.

RELATED APPLICATIONS

The present application is a continuation of U.S. patent applicationSer. No. 15/675,636 filed Aug. 11, 2017, now U.S. Pat. No. 10,463,288,which is a continuation of U.S. patent application Ser. No. 15/017,568filed Feb. 5, 2016, now U.S. Pat. No. 9,730,623, which is a continuationof U.S. patent application Ser. No. 14/270,332 filed May 5, 2014, whichis a continuation of U.S. patent application Ser. No. 13/729,075 filedDec. 28, 2012, now U.S. Pat. No. 8,718,739, which is a continuation ofU.S. patent application Ser. No. 12/363,712 filed Jan. 30, 2009, nowU.S. Pat. No. 8,346,335, which claims priority under 35 U.S.C. § 119(e)to U.S. Provisional Application No. 61/040,633 filed Mar. 28, 2008entitled “Analyte Sensor Calibration Management,” and assigned to theassignee of the present application, Abbott Diabetes Care Inc. ofAlameda, Calif., the disclosures of each of which are incorporatedherein by reference for all purposes.

BACKGROUND

The detection of the level of glucose or other analytes, such aslactate, oxygen or the like, in certain individuals is vitally importantto their health. For example, the monitoring of glucose is particularlyimportant to individuals with diabetes. Diabetics may need to monitorglucose levels to determine when insulin is needed to reduce glucoselevels in their bodies or when additional glucose is needed to raise thelevel of glucose in their bodies.

Devices have been developed for continuous or automatic monitoring ofanalytes, such as glucose, in bodily fluid such as in the blood streamor in interstitial fluid. Some of these analyte measuring devices areconfigured so that at least a portion of the devices are positionedbelow a skin surface of a user, e.g., in a blood vessel or in thesubcutaneous tissue of a user.

Following the sensor insertion, the resulting potential trauma to theskin and/or underlying tissue, for example, by the sensor introducerand/or the sensor itself, may, at times, result in instability ofsignals monitored by the sensor. This may occur in a number of analytesensors, but not in all cases. This instability is characterized by adecrease in the sensor signal, and when this occurs, generally, theanalyte levels monitored may not be reported, recorded or output to theuser.

Proper calibration of an analyte sensor with a reference glucosemeasurement or reading is important for accurate sensor performance.Calibration is a process by which a conversion factor (or sensitivity)is determined and represented, in its simplest form, as a ratio of theelectrical current generated by the analyte sensor to the referenceblood glucose value (for example, from an in vitro blood glucose meter)associated in time (for example, relatively time corresponding) with thecurrent signal from the analyte sensor. Ideally, the sensitivity isconstant throughout the life of the analyte sensor when positioned influid contact with an analyte of a user (such as interstitial fluid). Inpractice, however, the sensitivity may vary over time. It has beenobserved that a depression or attenuation in the sensitivity, usuallyfollowing a predetermined time period measured from the insertion orpositioning of the analyte sensor, occurs sometimes for up to 24 hoursfor some analyte sensors. This signal characteristic is referred to asEarly Sensitivity Attenuation (ESA) or referred to as ESA condition. TheESA condition may be a result of a physiological response to theintroduction of the analyte sensor to the subcutaneous tissue, and maybe present for any subcutaneously inserted analyte sensor.

Generally, the use of a standard calibration sensitivity calculationdoes not address the signal attenuation. A typical standard calibrationdoes not detect or manage the attenuated signal characteristics, andalso may potentially update or modify the calibration sensitivity usingthe erroneous and attenuated sensor signal. When sensor calibration isperformed while the sensor is undergoing a signal attenuation event, thereported or resulting sensor data may be erroneously high when thesensor sensitivity has recovered after the termination of the signalattenuation event. Such high biased results may be clinically unsafe, asthey may lead to missed hypoglycaemic events, or overdoses of medicationsuch as insulin. On the other hand, when sensor calibration is performedprior to an early signal attenuation event, erroneously low biasedsensor data will likely result during the period of the sensorsensitivity depression. Such low glucose results may, depending on themagnitude of the early signal attenuation event, result in falsehypoglycaemia alarms or missed hyperglycaemic events.

Another approach has been to delay the sensor calibration until afterthe early signal attenuation period measured, for example, from theinitial sensor insertion in the patient. However, this approach preventsthe reporting of the potentially erroneous analyte level monitored fromthe sensor during this period, but results in low data yield due to theundesirable delay for the display or reporting of the monitored analytelevels from the sensors regardless of whether or not early signalattenuation is present.

SUMMARY

Embodiments of the subject disclosure include device and methods ofdetecting a change, e.g., a decrease (or monitoring for a change in thesignal level), in sensitivity associated with an analyte sensor toidentify or detect early signal attenuation (ESA). The detected ormonitored analyte level is reported or output after a short sensorequilibration time period (e.g., approximately one hour or more or less)when detected change is not associated with early signal attenuation.

Also provided are systems, computer program products, and kits.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a block diagram of an embodiment of a data monitoring andmanagement system according to the present disclosure;

FIG. 2 shows a block diagram of an embodiment of the transmitter unit ofthe data monitoring and management system of FIG. 1;

FIG. 3 shows a block diagram of an embodiment of the receiver/monitorunit of the data monitoring and management system of FIG. 1;

FIG. 4 shows a schematic diagram of an embodiment of an analyte sensoraccording to the present disclosure;

FIGS. 5A-5B show a perspective view and a cross sectional view,respectively of an embodiment the analyte sensor of FIG. 4;

FIG. 6 is a flowchart illustrating an overall analyte sensor calibrationmanagement in accordance with one embodiment of the present disclosure;

FIG. 7 is a flowchart illustrating early signal attenuation (ESA)detection routine of FIG. 6 in accordance with one aspect of the presentdisclosure;

FIG. 8 is a flowchart illustrating early signal attenuation (ESA)categorization routine of FIG. 6 in accordance with one aspect of thepresent disclosure; and

FIG. 9 is a flowchart illustrating early signal attenuation (ESA)management routine of FIG. 6 in accordance with one aspect of thepresent disclosure.

DETAILED DESCRIPTION

Within the scope of the present disclosure, early signal attenuation(ESA) condition which may be attributable to associated instability ofmonitored analyte levels resulting from skin and/or tissue trauma whenthe sensor is transcutaneously positioned under the skin layer of auser. Analyte sensors may be manufactured and/or the trauma resultingfrom the inserted sensor may be such that the sensor attains a stabilitypoint or an equilibration level after a relatively short time period—forexample, within approximately one hour (or less) from the initial sensorinsertion.

In one aspect, the signals from the analyte sensor may be monitored forESA condition detection. When no ESA condition is detected and/or thesensor reaches the equilibration level within the short time period,then the analyte monitoring system may be configured to request areference blood glucose value from the user, for example, a fingerstickin vitro test using a blood glucose meter, to calibrate the sensorsignals, and thereafter, report or display to the user the monitoredanalyte levels. In this manner, in one aspect, the initial baselinecalibration of the analyte sensor may be performed after approximatelyone hour from the initial sensor insertion, and upon successfulcalibration, the resulting real time analyte levels displayed to theuser, or otherwise stored or logged in the analyte monitoring systemand/or transmitted to a remote device or terminal.

When the potential for ESA condition or actual ESA condition is detectedafter the initial equilibration time period, for example, ofapproximately one hour from the sensor insertion, the analyte monitoringsystem may be configured to alert the user to wait a predetermined timeperiod before providing the reference blood glucose value to provide thesensor to stabilize, or alternatively, the user may be prompted toprovide the reference blood glucose value to confirm whether thepotential ESA condition monitored is an actual occurrence of ESAcondition.

In one aspect, the scheduled calibration of the analyte sensor may bedelayed to provide the sensor with an additional time period to reach adesired or acceptable stability level. Among other conditions,boundaries may be established to provide the sensor with an additionaltime period to reach a predetermined or acceptable stability levelbefore the received analyte sensor signals are calibrated, and thus,provided to the user. Within the scope of the present disclosure, otherconditions and parameters may be provided to establish or detect ESAcondition during a predetermined time period from the initial sensorinsertion, for example, during the first 24 hours of sensor insertion.

In this manner, in one aspect, when it is determined that thetranscutaneously positioned sensor has reached an acceptable stabilitylevel resulting in the desired or predetermined equilibration level, theanalyte monitoring system may display or otherwise accept, output, log,or process the monitored analyte level, substantially in real time,received from the transcutaneously positioned sensor. In one aspect, theacceptable stability level is analyzed at approximately one hour fromthe initial sensor insertion, and thereafter, if no ESA condition isdetected, the analyte sensor data is calibrated against a referenceblood glucose value (for example, received from an in vitro glucosemeter).

In the case where ESA condition or the potential for such signalattenuation is detected, the analyte monitoring system may be configuredin one embodiment to perform one or more routines or functions to verifythe sensor related signals to confirm the ESA condition, to notify theuser to refrain from performing a fingerstick test using a blood glucosemeter to provide a reference blood glucose value for calibration, amongothers.

Before the present disclosure is described in additional detail, it isto be understood that this disclosure is not limited to particularembodiments described, as such may, of course, vary. It is also to beunderstood that the terminology used herein is for the purpose ofdescribing particular embodiments only, and is not intended to belimiting, since the scope of the present disclosure will be limited onlyby the appended claims.

Where a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit unlessthe context clearly dictates otherwise, between the upper and lowerlimit of that range and any other stated or intervening value in thatstated range, is encompassed within the disclosure. The upper and lowerlimits of these smaller ranges may independently be included in thesmaller ranges is also encompassed within the disclosure, subject to anyspecifically excluded limit in the stated range. Where the stated rangeincludes one or both of the limits, ranges excluding either or both ofthose included limits are also included in the disclosure.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this disclosure belongs. Although any methods andmaterials similar or equivalent to those described herein can also beused in the practice or testing of the present disclosure, the preferredmethods and materials are now described. All publications mentionedherein are incorporated herein by reference to disclose and describe themethods and/or materials in connection with which the publications arecited.

It must be noted that as used herein and in the appended claims, thesingular forms “a”, “an”, and “the” include plural referents unless thecontext clearly dictates otherwise.

The publications discussed herein are provided solely for theirdisclosure prior to the filing date of the present application. Nothingherein is to be construed as an admission that the present disclosure isnot entitled to antedate such publication by virtue of prior disclosure.Further, the dates of publication provided may be different from theactual publication dates which may need to be independently confirmed.

As will be apparent to those of skill in the art upon reading thisdisclosure, each of the individual embodiments described and illustratedherein has discrete components and features which may be readilyseparated from or combined with the features of any of the other severalembodiments without departing from the scope or spirit of the presentdisclosure.

The figures shown herein are not necessarily drawn to scale, with somecomponents and features being exaggerated for clarity.

Generally, embodiments of the present disclosure relate to methods anddevices for detecting at least one analyte such as glucose in bodyfluid. In certain embodiments, the present disclosure relates to thecontinuous and/or automatic in vivo monitoring of the level of ananalyte using an analyte sensor.

Accordingly, embodiments include analyte monitoring devices and systemsthat include an analyte sensor—at least a portion of which ispositionable beneath the skin of the user—for the in vivo detection, ofan analyte, such as glucose, lactate, and the like, in a body fluid.Embodiments include wholly implantable analyte sensors and analytesensors in which only a portion of the sensor is positioned under theskin and a portion of the sensor resides above the skin, e.g., forcontact to a transmitter, receiver, transceiver, processor, etc. Thesensor may be, for example, subcutaneously positionable in a patient forthe continuous or periodic monitoring of a level of an analyte in apatient's interstitial fluid. For the purposes of this description,continuous monitoring and periodic monitoring will be usedinterchangeably, unless noted otherwise. The analyte level may becorrelated and/or converted to analyte levels in blood or other fluids.In certain embodiments, an analyte sensor may be positioned in contactwith interstitial fluid to detect the level of glucose, which detectedglucose may be used to infer the glucose level in the patient'sbloodstream. Analyte sensors may be insertable into a vein, artery, orother portion of the body containing fluid. Embodiments of the analytesensors of the subject disclosure may be configured for monitoring thelevel of the analyte over a time period which may range from minutes,hours, days, weeks, or longer.

Of interest are analyte sensors, such as glucose sensors, that arecapable of in vivo detection of an analyte for about one hour or more,e.g., about a few hours or more, e.g., about a few days or more, e.g.,about three days or more, e.g., about five days or more, e.g., aboutseven days or more, e.g., about several weeks or at least one month.Future analyte levels may be predicted based on information obtained,e.g., the current analyte level at time to, the rate of change of theanalyte, etc. Predictive alarms may notify the user of predicted analytelevels that may be of concern prior to or in advance of the analytelevel reaching the future level. This enables the user an opportunity totake corrective action.

FIG. 1 shows a data monitoring and management system such as, forexample, an analyte (e.g., glucose) monitoring system 100 in accordancewith certain embodiments. Embodiments of the subject disclosure arefurther described primarily with respect to glucose monitoring devicesand systems, and methods of glucose detection, for convenience only andsuch description is in no way intended to limit the scope of thedisclosure. It is to be understood that the analyte monitoring systemmay be configured to monitor a variety of analytes at the same time orat different times.

Analytes that may be monitored include, but are not limited to, acetylcholine, amylase, bilirubin, cholesterol, chorionic gonadotropin,creatine kinase (e.g., CK-MB), creatine, DNA, fructosamine, glucose,glutamine, growth hormones, hormones, ketones, lactate, peroxide,prostate-specific antigen, prothrombin, RNA, thyroid stimulatinghormone, and troponin. The concentration of drugs, such as, for example,antibiotics (e.g., gentamicin, vancomycin, and the like), digitoxin,digoxin, drugs of abuse, theophylline, and warfarin, may also bemonitored. In those embodiments that monitor more than one analyte, theanalytes may be monitored at the same or different times.

The analyte monitoring system 100 includes a sensor 101, a dataprocessing unit 102 connectable to the sensor 101, and a primaryreceiver unit 104 which is configured to communicate with the dataprocessing unit 102 via a communication link 103. In certainembodiments, the primary receiver unit 104 may be further configured totransmit data to a data processing terminal 105 to evaluate or otherwiseprocess or format data received by the primary receiver unit 104. Thedata processing terminal 105 may be configured to receive data directlyfrom the data processing unit 102 via a communication link which mayoptionally be configured for bi-directional communication. Further, thedata processing unit 102 may include a transmitter or a transceiver totransmit and/or receive data to and/or from the primary receiver unit104, the data processing terminal 105 or optionally the secondaryreceiver unit 106.

Also shown in FIG. 1 is an optional secondary receiver unit 106 which isoperatively coupled to the communication link and configured to receivedata transmitted from the data processing unit 102. The secondaryreceiver unit 106 may be configured to communicate with the primaryreceiver unit 104, as well as the data processing terminal 105. Thesecondary receiver unit 106 may be configured for bi-directionalwireless communication with each of the primary receiver unit 104 andthe data processing terminal 105. As discussed in further detail below,in certain embodiments the secondary receiver unit 106 may be ade-featured receiver as compared to the primary receiver, i.e., thesecondary receiver may include a limited or minimal number of functionsand features as compared with the primary receiver unit 104. As such,the secondary receiver unit 106 may include a smaller (in one or more,including all, dimensions), compact housing or embodied in a device suchas a wrist watch, arm band, etc., for example. Alternatively, thesecondary receiver unit 106 may be configured with the same orsubstantially similar functions and features as the primary receiverunit 104. The secondary receiver unit 106 may include a docking portionto be mated with a docking cradle unit for placement by, e.g., thebedside for night time monitoring, and/or bi-directional communicationdevice.

Only one sensor 101, data processing unit 102 and data processingterminal 105 are shown in the embodiment of the analyte monitoringsystem 100 illustrated in FIG. 1. However, it will be appreciated by oneof ordinary skill in the art that the analyte monitoring system 100 mayinclude more than one sensor 101 and/or more than one data processingunit 102, and/or more than one data processing terminal 105. Multiplesensors may be positioned in a patient for analyte monitoring at thesame or different times. In certain embodiments, analyte informationobtained by a first positioned sensor may be employed as a comparison toanalyte information obtained by a second sensor. This may be useful toconfirm or validate analyte information obtained from one or both of thesensors. Such redundancy may be useful if analyte information iscontemplated in critical therapy-related decisions. In certainembodiments, a first sensor may be used to calibrate a second sensor.

The analyte monitoring system 100 may be a continuous monitoring system,or semi-continuous, or a discrete monitoring system. In amulti-component environment, each component may be configured to beuniquely identified by one or more of the other components in the systemso that communication conflict may be readily resolved between thevarious components within the analyte monitoring system 100. Forexample, unique IDs, communication channels, and the like, may be used.

In certain embodiments, the sensor 101 is physically positioned in or onthe body of a user whose analyte level is being monitored. The sensor101 may be configured to at least periodically sample the analyte levelof the user and convert the sampled analyte level into a correspondingsignal for transmission by the data processing unit 102. The dataprocessing unit 102 is coupleable to the sensor 101 so that both devicesare positioned in or on the user's body, with at least a portion of theanalyte sensor 101 positioned transcutaneously. The data processing unit102 performs data processing functions, where such functions may includebut are not limited to, filtering and encoding of data signals, each ofwhich corresponds to a sampled analyte level of the user, fortransmission to the primary receiver unit 104 via the communication link103. In one embodiment, the sensor 101 or the data processing unit 102or a combined sensor/data processing unit may be wholly implantableunder the skin layer of the user.

In one aspect, the primary receiver unit 104 may include an analoginterface section including an RF receiver and an antenna that isconfigured to communicate with the data processing unit 102 via thecommunication link 103, data processing unit 102 and a data processingsection for processing the received data from the data processing unit102 such as data decoding, error detection and correction, data clockgeneration, and/or data bit recovery.

In operation, the primary receiver unit 104 in certain embodiments isconfigured to synchronize with the data processing unit 102 to uniquelyidentify the data processing unit 102, based on, for example, anidentification information of the data processing unit 102, andthereafter, to periodically receive signals transmitted from the dataprocessing unit 102 associated with the monitored analyte levelsdetected by the sensor 101.

Referring again to FIG. 1, the data processing terminal 105 may includea personal computer, a portable computer such as a laptop or a handhelddevice (e.g., personal digital assistants (PDAs), telephone such as acellular phone (e.g., a multimedia and Internet-enabled mobile phonesuch as an iPhone or similar phone), mp3 player, pager, and the like),drug delivery device, each of which may be configured for datacommunication with the receiver via a wired or a wireless connection.Additionally, the data processing terminal 105 may further be connectedto a data network (not shown) for storing, retrieving, updating, and/oranalyzing data corresponding to the detected analyte level of the user.

The data processing terminal 105 may include an infusion device such asan insulin infusion pump or the like, which may be configured toadminister insulin to patients, and which may be configured tocommunicate with the primary receiver unit 104 for receiving, amongothers, the measured analyte level. Alternatively, the primary receiverunit 104 may be configured to integrate an infusion device therein sothat the primary receiver unit 104 is configured to administer insulin(or other appropriate drug) therapy to patients, for example, foradministering and modifying basal profiles, as well as for determiningappropriate boluses for administration based on, among others, thedetected analyte levels received from the data processing unit 102. Aninfusion device may be an external device or an internal device (whollyimplantable in a user).

In particular embodiments, the data processing terminal 105, which mayinclude an insulin pump, may be configured to receive the analytesignals from the data processing unit 102, and thus, incorporate thefunctions of the primary receiver unit 104 including data processing formanaging the patient's insulin therapy and analyte monitoring. Incertain embodiments, the communication link 103 as well as one or moreof the other communication interfaces shown in FIG. 1 may use one ormore of an RF communication protocol, an infrared communicationprotocol, a Bluetooth® enabled communication protocol, an 802.11xwireless communication protocol, or an equivalent wireless communicationprotocol which would allow secure, wireless communication of severalunits (for example, per HIPAA requirements) while avoiding potentialdata collision and interference.

FIG. 2 is a block diagram of the data processing unit of the datamonitoring and detection system shown in FIG. 1 in accordance withcertain embodiments. The data processing unit 102 thus may include oneor more of an analog interface 201 configured to communicate with thesensor 101 (FIG. 1), a user input 202, and a temperature detectionsection 203, each of which is operatively coupled to a transmitterprocessor 204 such as a central processing unit (CPU). The transmittermay include user input and/or interface components or may be free ofuser input and/or interface components.

Further shown in FIG. 2 are serial communication section 205 and an RFtransmitter 206, each of which is also operatively coupled to thetransmitter processor 204. Also shown in FIG. 2 is a dedicated link 209from the analog interface 201 to serial communication section 205.Moreover, a power supply 207, such as a battery, may also be provided inthe data processing unit 102 to provide the necessary power for the dataprocessing unit 102. Additionally, as can be seen from the Figure, clock208 may be provided to, among others, supply real time information tothe transmitter processor 204.

As can be seen in the embodiment of FIG. 2, the sensor 101 (FIG. 1)includes four contacts, three of which are electrodes—work electrode (W)210, guard contact (G) 211, reference electrode (R) 212, and counterelectrode (C) 213, each operatively coupled to the analog interface 201of the data processing unit 102. In certain embodiments, each of thework electrode (W) 210, guard contact (G) 211, reference electrode (R)212, and counter electrode (C) 213 may be made using a conductivematerial that may be applied by, e.g., chemical vapor deposition (CVD),physical vapor deposition, sputtering, reactive sputtering, printing,coating, ablating (e.g., laser ablation), painting, dip coating,etching, and the like. Materials include, but are not limited to,aluminum, carbon (such as graphite), cobalt, copper, gallium, gold,indium, iridium, iron, lead, magnesium, mercury (as an amalgam), nickel,niobium, osmium, palladium, platinum, rhenium, rhodium, selenium,silicon (e.g., doped polycrystalline silicon), silver, tantalum, tin,titanium, tungsten, uranium, vanadium, zinc, zirconium, mixturesthereof, and alloys, oxides, or metallic compounds of these elements.

The processor 204 may be configured to generate and/or process controlsignals to the various sections of the data processing unit 102 duringthe operation of the data processing unit 102. In certain embodiments,the processor 204 also includes memory (not shown) for storing data suchas the identification information for the data processing unit 102, aswell as the data associated with signals received from the sensor 101.The stored information may be retrieved and processed for transmissionto the primary receiver unit 104 under the control of the processor 204.Furthermore, the power supply 207 may include a commercially availablebattery.

In certain embodiments, a manufacturing process of the data processingunit 102 may place the data processing unit 102 in the lower power,non-operating state (i.e., post-manufacture sleep mode). In this manner,the shelf life of the data processing unit 102 may be significantlyimproved. Moreover, as shown in FIG. 2, while the power supply unit 207is shown as coupled to the processor 204, and as such, the processor 204is configured to provide control of the power supply unit 207, it shouldbe noted that within the scope of the present disclosure, the powersupply unit 207 is configured to provide the necessary power to each ofthe components of the data processing unit 102 shown in FIG. 2.

Referring back to FIG. 2, the power supply section 207 of the dataprocessing unit 102 in one embodiment may include a rechargeable batteryunit that may be recharged by a separate power supply recharging unit(for example, provided in the receiver unit 104) so that the dataprocessing unit 102 may be powered for a longer period of usage time. Incertain embodiments, the data processing unit 102 may be configuredwithout a battery in the power supply section 207, in which case thedata processing unit 102 may be configured to receive power from anexternal power supply source (for example, a battery, electrical outlet,etc.) as discussed in further detail below.

Referring yet again to FIG. 2, a temperature detection section 203 ofthe data processing unit 102 is configured to monitor the temperature ofthe skin near the sensor insertion site. The temperature reading may beused to adjust the analyte readings obtained from the analog interface201. Also shown is a leak detection circuit 214 coupled to the guardcontact (G) 211 and the processor 204 in the data processing unit 102 ofthe data monitoring and management system 100. The leak detectioncircuit 214 may be configured to detect leakage current in the sensor101 to determine whether the measured sensor data are corrupt or whetherthe measured data from the sensor 101 is accurate. Such detection maytrigger a notification to the user.

FIG. 3 is a block diagram of the receiver/monitor unit such as theprimary receiver unit 104 of the data monitoring and management systemshown in FIG. 1 in accordance with certain embodiments. The primaryreceiver unit 104 includes one or more of: a blood glucose test stripinterface 301, an RF receiver 302, an input 303, a temperature detectionsection 304, and a clock 305, each of which is operatively coupled to aprocessing and storage section 307. The primary receiver unit 104 alsoincludes a power supply 306 operatively coupled to a power conversionand monitoring section 308. Further, the power conversion and monitoringsection 308 is also coupled to the receiver processor 307. Moreover,also shown are a receiver serial communication section 309, and anoutput 310, each operatively coupled to the processing and storage unit307. The receiver may include user input and/or interface components ormay be free of user input and/or interface components.

In certain embodiments, the test strip interface 301 includes a glucoselevel testing portion to receive a blood (or other body fluid sample)glucose test or information related thereto. For example, the interfacemay include a test strip port to receive a glucose test strip. Thedevice may determine the glucose level of the test strip, and optionallydisplay (or otherwise notice) the glucose level on the output 310 of theprimary receiver unit 104. Any suitable test strip may be employed,e.g., test strips that only require a very small amount (e.g., onemicroliter or less, e.g., 0.5 microliter or less, e.g., 0.1 microliteror less), of applied sample to the strip in order to obtain accurateglucose information, e.g. FreeStyle® blood glucose test strips fromAbbott Diabetes Care Inc. Glucose information obtained by the in vitroglucose testing device may be used for a variety of purposes,computations, etc. For example, the information may be used to calibratesensor 101, confirm results of the sensor 101 to increase the confidencethereof (e.g., in instances in which information obtained by sensor 101is employed in therapy related decisions), etc.

In one aspect, the RF receiver 302 is configured to communicate, via thecommunication link 103 (FIG. 1) with the RF transmitter 206 of the dataprocessing unit 102, to receive encoded data from the data processingunit 102 for, among others, signal mixing, demodulation, and other dataprocessing. The input 303 of the primary receiver unit 104 is configuredto allow the user to enter information into the primary receiver unit104 as needed. In one aspect, the input 303 may include keys of akeypad, a touch-sensitive screen, and/or a voice-activated input commandunit, and the like. The temperature monitor section 304 may beconfigured to provide temperature information of the primary receiverunit 104 to the processing and storage section 307, while the clock 305provides, among others, real time or clock information to the processingand storage section 307.

Each of the various components of the primary receiver unit 104 shown inFIG. 3 is powered by the power supply 306 (or other power supply) which,in certain embodiments, includes a battery. Furthermore, the powerconversion and monitoring section 308 is configured to monitor the powerusage by the various components in the primary receiver unit 104 foreffective power management and may alert the user, for example, in theevent of power usage which renders the primary receiver unit 104 insub-optimal operating conditions. The serial communication section 309in the primary receiver unit 104 is configured to provide abi-directional communication path from the testing and/or manufacturingequipment for, among others, initialization, testing, and configurationof the primary receiver unit 104. Serial communication section 309 canalso be used to upload data to a computer, such as time-stamped bloodglucose data. The communication link with an external device (not shown)can be made, for example, by cable (such as USB or serial cable),infrared (IR) or RF link. The output/display 310 of the primary receiverunit 104 is configured to provide, among others, a graphical userinterface (GUI), and may include a liquid crystal display (LCD) fordisplaying information. Additionally, the output/display 310 may alsoinclude an integrated speaker for outputting audible signals as well asto provide vibration output as commonly found in handheld electronicdevices, such as mobile telephones, pagers, etc. In certain embodiments,the primary receiver unit 104 also includes an electro-luminescent lampconfigured to provide backlighting to the output 310 for output visualdisplay in dark ambient surroundings.

Referring back to FIG. 3, the primary receiver unit 104 may also includea storage section such as a programmable, non-volatile memory device aspart of the processor 307, or provided separately in the primaryreceiver unit 104, operatively coupled to the processor 307. Theprocessor 307 may be configured to perform Manchester decoding (or otherprotocol(s)) as well as error detection and correction upon the encodeddata received from the data processing unit 102 via the communicationlink 103.

In further embodiments, the data processing unit 102 and/or the primaryreceiver unit 104 and/or the secondary receiver unit 106, and/or thedata processing terminal/infusion section 105 may be configured toreceive the blood glucose value wirelessly over a communication linkfrom, for example, a blood glucose meter. In further embodiments, a usermanipulating or using the analyte monitoring system 100 (FIG. 1) maymanually input the blood glucose value using, for example, a userinterface (for example, a keyboard, keypad, voice commands, and thelike) incorporated in the one or more of the data processing unit 102,the primary receiver unit 104, secondary receiver unit 106, or the dataprocessing terminal/infusion section 105.

Additional detailed descriptions of embodiments of the continuousanalyte monitoring system, embodiments of its various components areprovided in U.S. Pat. No. 6,175,752 issued Jan. 16, 2001 entitled“Analyte Monitoring Device and Methods of Use”, and in U.S. patentapplication Ser. No. 10/745,878 filed Dec. 26, 2003, issued as U.S. Pat.No. 7,811,231, entitled “Continuous Glucose Monitoring System andMethods of Use”, each assigned to the Assignee of the presentapplication.

FIG. 4 schematically shows an embodiment of an analyte sensor inaccordance with the present disclosure. The sensor 400 includeselectrodes 401, 402 and 403 on a base 404. The sensor may be whollyimplantable in a user or may be configured so that only a portion ispositioned within (internal) a user and another portion outside(external) a user. For example, the sensor 400 may include a portionpositionable above a surface of the skin 410, and a portion positionedbelow the skin. In such embodiments, the external portion may includecontacts (connected to respective electrodes of the second portion bytraces) to connect to another device also external to the user such as atransmitter unit. While the embodiment of FIG. 4 shows three electrodesside-by-side on the same surface of base 404, other configurations arecontemplated, e.g., fewer or greater electrodes, some or all electrodeson different surfaces of the base or present on another base, some orall electrodes stacked together, electrodes of differing materials anddimensions, etc.

FIG. 5A shows a perspective view of an embodiment of an electrochemicalanalyte sensor 500 having a first portion (which in this embodiment maybe characterized as a major portion) positionable above a surface of theskin 510, and a second portion (which in this embodiment may becharacterized as a minor portion) that includes an insertion tip 530positionable below the skin, e.g., penetrating through the skin andinto, e.g., the subcutaneous space 520, in contact with the user'sbiofluid such as interstitial fluid. Contact portions of a workingelectrode 501, a reference electrode 502, and a counter electrode 503are positioned on the portion of the sensor 500 situated above the skinsurface 510. Working electrode 501, a reference electrode 502, and acounter electrode 503 are shown at the second section and particularlyat the insertion tip 530. Traces may be provided from the electrode atthe tip to the contact, as shown in FIG. 5A. It is to be understood thatgreater or fewer electrodes may be provided on a sensor. For example, asensor may include more than one working electrode and/or the counterand reference electrodes may be a single counter/reference electrode,etc.

FIG. 5B shows a cross sectional view of a portion of the sensor 500 ofFIG. 5A. The electrodes 501, 502 and 503, of the sensor 500 as well asthe substrate and the dielectric layers are provided in a layeredconfiguration or construction. For example, as shown in FIG. 5B, in oneaspect, the sensor 500 (such as the sensor 101 FIG. 1), includes asubstrate layer 504, and a first conducting layer 501 such as carbon,gold, etc., disposed on at least a portion of the substrate layer 504,and which may provide the working electrode. Also shown disposed on atleast a portion of the first conducting layer 501 is a sensing layer508.

Referring back to FIG. 5B, a first insulation layer such as a firstdielectric layer 505 is disposed or layered on at least a portion of thefirst conducting layer 501, and further, a second conducting layer 509may be disposed or stacked on top of at least a portion of the firstinsulation layer (or dielectric layer) 505. As shown in FIG. 5B, thesecond conducting layer 509 may provide the reference electrode 502, andin one aspect, may include a layer of silver/silver chloride (Ag/AgCl),gold, etc.

Referring still again to FIG. 5B, a second insulation layer 506 such asa dielectric layer in one embodiment may be disposed or layered on atleast a portion of the second conducting layer 509. Further, a thirdconducting layer 503 may provide the counter electrode 503. It may bedisposed on at least a portion of the second insulation layer 506.Finally, a third insulation layer 507 may be disposed or layered on atleast a portion of the third conducting layer 503. In this manner, thesensor 500 may be layered such that at least a portion of each of theconducting layers is separated by a respective insulation layer (forexample, a dielectric layer).

The embodiment of FIGS. 5A and 5B show the layers having differentlengths. Some or all of the layers may have the same or differentlengths and/or widths.

In certain embodiments, some or all of the electrodes 501, 502, 503 maybe provided on the same side of the substrate 504 in the layeredconstruction as described above, or alternatively, may be provided in aco-planar manner such that two or more electrodes may be positioned onthe same plane (e.g., side-by side (e.g., parallel) or angled relativeto each other) on the substrate 504. For example, co-planar electrodesmay include a suitable spacing there between and/or include dielectricmaterial or insulation material disposed between the conductinglayers/electrodes. Furthermore, in certain embodiments one or more ofthe electrodes 501, 502, 503 may be disposed on opposing sides of thesubstrate 504. In such embodiments, contact pads may be on the same ordifferent sides of the substrate. For example, an electrode may be on afirst side and its respective contact may be on a second side, e.g., atrace connecting the electrode and the contact may traverse through thesubstrate.

In certain embodiments, the data processing unit 102 may be configuredto perform sensor insertion detection and data quality analysis,information pertaining to which may also be transmitted to the primaryreceiver unit 104 periodically at the predetermined time interval. Inturn, the primary receiver unit 104 may be configured to perform, forexample, skin temperature compensation/correction as well as calibrationof the sensor data received from the data processing unit 102.

As noted above, analyte sensors may include an analyte-responsive enzymein a sensing layer. Some analytes, such as oxygen, can be directlyelectrooxidized or electroreduced on a sensor, and more specifically atleast on a working electrode of a sensor. Other analytes, such asglucose and lactate, require the presence of at least one electrontransfer agent and/or at least one catalyst to facilitate theelectrooxidation or electroreduction of the analyte. Catalysts may alsobe used for analytes, such as oxygen, that can be directlyelectrooxidized or electroreduced on the working electrode. For theseanalytes, each working electrode includes a sensing layer (see forexample sensing layer 508 of FIG. 5B) formed proximate to or on asurface of a working electrode. In many embodiments, a sensing layer isformed near or on only a small portion of at least a working electrode.

A variety of different sensing layer configurations may be used. Incertain embodiments, the sensing layer is deposited on the conductivematerial of a working electrode. The sensing layer may extend beyond theconductive material of the working electrode. In some cases, the sensinglayer may also extend over other electrodes, e.g., over the counterelectrode and/or reference electrode (or counter/reference is provided).The sensing layer may be integral with the material of an electrode.

A sensing layer that is in direct contact with the working electrode maycontain an electron transfer agent to transfer electrons directly orindirectly between the analyte and the working electrode, and/or acatalyst to facilitate a reaction of the analyte.

A sensing layer that is not in direct contact with the working electrodemay include a catalyst that facilitates a reaction of the analyte.However, such sensing layers may not include an electron transfer agentthat transfers electrons directly from the working electrode to theanalyte, as the sensing layer is spaced apart from the workingelectrode. One example of this type of sensor is a glucose or lactatesensor which includes an enzyme (e.g., glucose oxidase, glucosedehydrogenase, lactate oxidase, and the like) in the sensing layer. Theglucose or lactate may react with a second compound in the presence ofthe enzyme. The second compound may then be electrooxidized orelectroreduced at the electrode. Changes in the signal at the electrodeindicate changes in the level of the second compound in the fluid andare proportional to changes in glucose or lactate level and, thus,correlate to the analyte level.

In certain embodiments which include more than one working electrode,one or more of the working electrodes do not have a correspondingsensing layer, or have a sensing layer which does not contain one ormore components (e.g., an electron transfer agent and/or catalyst)needed to electrolyze the analyte. Thus, the signal at this workingelectrode corresponds to background signal which may be removed from theanalyte signal obtained from one or more other working electrodes thatare associated with fully-functional sensing layers by, for example,subtracting the signal.

In certain embodiments, the sensing layer includes one or more electrontransfer agents. Electron transfer agents that may be employed areelectroreducible and electrooxidizable ions or molecules having redoxpotentials that are a few hundred millivolts above or below the redoxpotential of the standard calomel electrode (SCE). The electron transferagent may be organic, organometallic, or inorganic.

In certain embodiments, electron transfer agents have structures orcharges which prevent or substantially reduce the diffusional loss ofthe electron transfer agent during the period of time that the sample isbeing analyzed. For example, electron transfer agents include but arenot limited to a redox species, e.g., bound to a polymer which can inturn be disposed on or near the working electrode. The bond between theredox species and the polymer may be covalent, coordinative, or ionic.Although any organic or organometallic redox species may be bound to apolymer and used as an electron transfer agent, in certain embodimentsthe redox species is a transition metal compound or complex, e.g.,osmium, ruthenium, iron, and cobalt compounds or complexes. It will berecognized that many redox species described for use with a polymericcomponent may also be used, without a polymeric component.

One type of polymeric electron transfer agent contains a redox speciescovalently bound in a polymeric composition. An example of this type ofmediator is poly(vinylferrocene). Another type of electron transferagent contains an ionically-bound redox species. This type of mediatormay include a charged polymer coupled to an oppositely charged redoxspecies. Examples of this type of mediator include a negatively chargedpolymer coupled to a positively charged redox species such as an osmiumor ruthenium polypyridyl cation. Another example of an ionically-boundmediator is a positively charged polymer such as quaternizedpoly(4-vinyl pyridine) or poly(l-vinyl imidazole) coupled to anegatively charged redox species such as ferricyanide or ferrocyanide.In other embodiments, electron transfer agents include a redox speciescoordinatively bound to a polymer. For example, the mediator may beformed by coordination of an osmium or cobalt 2,2′-bipyridyl complex topoly(l-vinyl imidazole) or poly(4-vinyl pyridine).

Suitable electron transfer agents are osmium transition metal complexeswith one or more ligands, each ligand having a nitrogen-containingheterocycle such as 2,2′-bipyridine, 1,10-phenanthroline, or derivativesthereof. The electron transfer agents may also have one or more ligandscovalently bound in a polymer, each ligand having at least onenitrogen-containing heterocycle, such as pyridine, imidazole, orderivatives thereof.

The present disclosure may employ electron transfer agents having aredox potential ranging from about −100 mV to about +150 mV versus thestandard calomel electrode (SCE), e.g., ranges from about −100 mV toabout +150 mV, e.g., ranges from about −50 mV to about +50 mV, e.g.,electron transfer agents have osmium redox centers and a redox potentialranging from +50 mV to −150 mV versus SCE.

The sensing layer may also include a catalyst which is capable ofcatalyzing a reaction of the analyte. The catalyst may also, in someembodiments, act as an electron transfer agent. One example of asuitable catalyst is an enzyme which catalyzes a reaction of theanalyte. For example, a catalyst, such as a glucose oxidase, glucosedehydrogenase (e.g., pyrroloquinoline quinone glucose dehydrogenase(PQQ)), or oligosaccharide dehydrogenase, may be used when the analyteof interest is glucose. A lactate oxidase or lactate dehydrogenase maybe used when the analyte of interest is lactate. Laccase may be usedwhen the analyte of interest is oxygen or when oxygen is generated orconsumed in response to a reaction of the analyte.

In certain embodiments, a catalyst may be attached to a polymer, crosslinking the catalyst with another electron transfer agent (which, asdescribed above, may be polymeric). A second catalyst may also be usedin certain embodiments. This second catalyst may be used to catalyze areaction of a product compound resulting from the catalyzed reaction ofthe analyte. The second catalyst may operate with an electron transferagent to electrolyze the product compound to generate a signal at theworking electrode. Alternatively, a second catalyst may be provided inan interferent-eliminating layer to catalyze reactions that removeinterferents.

Certain embodiments include a Wired Enzyme™ sensing layer that works ata gentle oxidizing potential, e.g., a potential of about +40 mV. Thissensing layer uses an osmium (Os)-based mediator designed for lowpotential operation and is stably anchored in a polymeric layer.Accordingly, in certain embodiments the sensing element is a redoxactive component that includes (1) Osmium-based mediator moleculesattached by stable (bidente) ligands anchored to a polymeric backbone,and (2) glucose oxidase enzyme molecules. These two constituents arecrosslinked together.

A mass transport limiting layer (not shown), e.g., an analyte fluxmodulating layer, may be included with the sensor to act as adiffusion-limiting barrier to reduce the rate of mass transport of theanalyte, for example, glucose or lactate, into the region around theworking electrodes. The mass transport limiting layers are useful inlimiting the flux of an analyte to a working electrode in anelectrochemical sensor so that the sensor is linearly responsive over alarge range of analyte concentrations and is easily calibrated. Masstransport limiting layers may include polymers and may be biocompatible.A mass transport limiting layer may serve many functions, e.g.,functionalities of a biocompatible layer and/or interferent-eliminatinglayer may be provided by the mass transport limiting layer.

In certain embodiments, a mass transport limiting layer is a membranecomposed of crosslinked polymers containing heterocyclic nitrogengroups, such as polymers of polyvinylpyridine and polyvinylimidazole.Electrochemical sensors equipped with such membranes have considerablesensitivity and stability, and a large signal-to-noise ratio, in avariety of conditions.

According to certain embodiments, a membrane is formed by crosslinkingin situ a polymer, modified with a zwitterionic moiety, a non-pyridinecopolymer component, and optionally another moiety that is eitherhydrophilic or hydrophobic, and/or has other desirable properties, in analcohol-buffer solution. The modified polymer may be made from aprecursor polymer containing heterocyclic nitrogen groups. Optionally,hydrophilic or hydrophobic modifiers may be used to “fine-tune” thepermeability of the resulting membrane to an analyte of interest.Optional hydrophilic modifiers, such as poly(ethylene glycol), hydroxylor polyhydroxyl modifiers, may be used to enhance the biocompatibilityof the polymer or the resulting membrane.

A biocompatible layer (not shown) may be provided over at least thatportion of the sensor which is subcutaneously inserted into the patient.The biocompatible layer may be incorporated in theinterferent-eliminating layer or in the mass transport limiting layer ormay be a separate layer. The layer may prevent the penetration of largebiomolecules into the electrodes. The biocompatible layer may alsoprevent protein adhesion to the sensor, formation of blood clots, andother undesirable interactions between the sensor and body. For example,a sensor may be completely or partially covered on its exterior with abiocompatible coating.

An interferent-eliminating layer (not shown) may be included in thesensor. The interferent-eliminating layer may be incorporated in thebiocompatible layer or in the mass transport limiting layer or may be aseparate layer. Interferents are molecules or other species that areelectroreduced or electrooxidized at the electrode, either directly orvia an electron transfer agent, to produce a false signal. In oneembodiment, a film or membrane prevents the penetration of one or moreinterferents into the region around the working electrode. In manyembodiments, this type of interferent-eliminating layer is much lesspermeable to one or more of the interferents than to the analyte. Aninterferent-eliminating layer may include ionic components to reduce thepermeability of the interferent-eliminating layer to ionic interferentshaving the same charge as the ionic components. Another example of aninterferent-eliminating layer includes a catalyst for catalyzing areaction which removes interferents.

A sensor may also include an active agent such as an anticlotting and/orantiglycolytic agent(s) disposed on at least a portion of a sensor thatis positioned in a user. An anticlotting agent may reduce or eliminatethe clotting of blood or other body fluid around the sensor,particularly after insertion of the sensor. Blood clots may foul thesensor or irreproducibly reduce the amount of analyte which diffusesinto the sensor. Examples of useful anticlotting agents include heparinand tissue plasminogen activator (TPA), as well as other knownanticlotting agents. Embodiments may include an antiglycolytic agent orprecursor thereof. The term “antiglycolytic” is used broadly herein toinclude any substance that at least retards glucose consumption ofliving cells.

Sensors described herein may be configured to require no systemcalibration or no user calibration. For example, a sensor may be factorycalibrated and need not require further calibrating. In certainembodiments, calibration may be required, but may be done without userintervention, i.e., may be automatic. In those embodiments in whichcalibration by the user is required, the calibration may be according toa predetermined schedule or may be dynamic, i.e., the time for which maybe determined by the system on a real-time basis according to variousfactors. Calibration may be accomplished using an in vitro test strip orother calibrator, e.g., a small sample test strip such as a test stripthat requires less than about 1 microliter of sample (for exampleFreeStyle® blood glucose monitoring test strips from Abbott DiabetesCare Inc.). For example, test strips that require less than about 1nanoliter of sample may be used. In certain embodiments, a sensor may becalibrated using only one sample of body fluid per calibration event.For example, a user need only lance a body part one time to obtainsample for a calibration event (e.g., for a test strip), or may lancemore than one time within a short period of time if an insufficientvolume of sample is obtained firstly. Embodiments include obtaining andusing multiple samples of body fluid for a given calibration event,where glucose values of each sample are substantially similar. Dataobtained from a given calibration event may be used independently tocalibrate or combined with data obtained from previous calibrationevents, e.g., averaged including weighted averaged, etc., to calibrate.

An analyte system may include an optional alarm system that, e.g., basedon information from a processor, warns the patient of a potentiallydetrimental condition of the analyte. For example, if glucose is theanalyte, an alarm system may warn a user of conditions such ashypoglycemia and/or hyperglycemia and/or impending hypoglycemia, and/orimpending hyperglycemia. An alarm system may be triggered when analytelevels reach or exceed a threshold value. An alarm system may also, oralternatively, be activated when the rate of change or acceleration ofthe rate of change in analyte level increase or decrease reaches orexceeds a threshold rate or acceleration. For example, in the case of aglucose monitoring system, an alarm system may be activated if the rateof change in glucose concentration exceeds a threshold value which mightindicate that a hyperglycemic or hypoglycemic condition is likely tooccur. A system may also include system alarms that notify a user ofsystem information such as battery condition, calibration, sensordislodgment, sensor malfunction, etc. Alarms may be, for example,auditory and/or visual. Other sensory-stimulating alarm systems may beused including alarm systems which heat, cool, vibrate, or produce amild electrical shock when activated.

The subject disclosure also includes sensors used in sensor-based drugdelivery systems. The system may provide a drug to counteract the highor low level of the analyte in response to the signals from one or moresensors. Alternatively, the system may monitor the drug concentration toensure that the drug remains within a desired therapeutic range. Thedrug delivery system may include one or more (e.g., two or more)sensors, a transmitter, a receiver/display unit, and a drugadministration system. In some cases, some or all components may beintegrated in a single unit. The sensor-based drug delivery system mayuse data from the one or more sensors to provide necessary input for acontrol algorithm/mechanism to adjust the administration of drugs, e.g.,automatically or semi-automatically. As an example, a glucose sensorcould be used to control and adjust the administration of insulin froman external or implanted insulin pump.

Returning to the Figures, as discussed above the sensitivity associatedwith the analyte sensor may be attenuated during the first 24 hours orso following the sensor insertion due to, for example, tissue trauma,and the like, potentially resulting in ESA condition for the analytesensor. Accordingly, in accordance with embodiments of the presentdisclosure, analyte sensor calibration management is provided toeffectively detect the occurrence of the sensor ESA condition, properlycategorizing it and thereafter, managing the ESA condition such thatpotentially false readings from the sensor are minimized while the timeperiod by which the reporting of the monitored analyte level from thesensor is initiated as close to the initial sensor insertion aspossible.

In one aspect, the analyte sensor calibration management routine may beconfigured to detect the presence of ESA condition, confirm the detectedESA event, and to manage calibration during the confirmed ESA event toensure optimal calibration sensitivity estimate.

In one aspect, the analyte sensor calibration management algorithmincludes three parts: (1) ESA detection, (2) ESA categorization, and (3)ESA management. Each aspect or part of the management algorithm isdiscussed in detail below.

In one aspect, the ESA detection component of the calibration managementalgorithm includes detection of the sensor signal (for example, the rawcurrent signal from the analyte sensor) and evaluating it forcharacteristics of ESA condition. If ESA condition is detected based onthis evaluation, a calibration of the analyte sensor is requested (forexample, by prompting the user to perform a fingerstick measurement andenter the resulting reference blood glucose measurement value) to obtaina sensitivity used to confirm the ESA event.

The ESA categorization aspect of the sensor calibration managementroutine in one aspect of the present disclosure includes rating theseverity of the possible attenuation in the analyte sensor signal basedon the sensitivities from the calibration measurements. In one aspect,the ESA categorization routine may classify the sensor signalcharacteristics into one of three categories: (a) No ESA (0), (b)Possible ESA (1), or (c) Likely ESA (2), based upon which, the ESAmanagement component of the calibration management routine, in oneaspect, performs additional processing to, for example, output theresulting monitored analyte level (for example, on the display of thereceiver unit 104/106 (FIG. 1)), or request additional reference bloodglucose measurements within a given time period, to verify that the ESAcondition is no longer present or insignificant.

More specifically, the ESA management routine of the calibrationmanagement algorithm, in one aspect, may be configured to either updatethe calibration sensitivity and report or display the monitored analytelevel from the sensor, update the calibration sensitivity andtemporarily report the monitored analyte level, or suspend reporting ofthe monitored analyte level, based, at least in part, on the ESAcategorization routine. In this manner, in one aspect of the presentdisclosure, there is provided an effective sensor calibration managementapproach that optimizes the analyte monitoring system accuracy andimproves user experience, based on, for example, maximizing data yield(reporting the monitored glucose level as early as possible from theinitial insertion), while minimizing the number of necessary calibrationattempts (for example, the need to perform in vitro blood glucosetesting).

More specifically, in one aspect, the ESA detection routine of thecalibration management algorithm may be configured to detect possibleESA events by evaluating various signal characteristics, includingsensor output, temperature, and/or elapsed time from sensor insertion.The ESA detection routine in one aspect evaluates the sensor signal forcharacteristics similar to those present or associated with ESA events,including, for example a depression or attenuation in the sensor signalduring the first 24 hours. The threshold for the ESA detection routinemay vary according to apriori knowledge of how the probability of theESA event may be correlated to other measurable quantities, and/oraccording to real-time revision of the likelihood of the ESA eventitself. An example of apriori knowledge may include the correlation ofthe probability of the ESA condition to elapsed time since the start ofsensor life (i.e., sensor insertion).

When the ESA detection routine determines that there is a highprobability that the sensor output is exhibiting ESA conditioncharacteristics, in one aspect, another calibration measurement (i.e.,fingerstick test) may be requested to be used to categorize and confirmthe ESA event. The calibration request timing and the sensor signalreporting following the ESA condition detection may vary depending onthe certainty or the likelihood of the ESA condition presence based onthe ESA detection routine.

For example, in one embodiment, if the ESA detection routine determinesthat the probability of ESA condition is high, then calibration may berequested immediately (for example, by prompting the user to performanother fingerstick test) and provide the reference blood glucosemeasurement value obtained, and the sensor representing the monitoredanalyte level are not reported to the user, but rather, withheld (forexample, by disabling, suspending or deactivating the display in thereceiver unit 104/106) until a calibration measurement can be performedto confirm the presence of ESA condition. On the other hand, if the ESAdetection routine determines that the likelihood of the presence of ESAcondition is less certain, sensor data corresponding to the monitoredanalyte level may be reported or displayed to the user on a conditionalbasis, and additional calibrations may be requested at a later scheduledtime if the attenuated signal characteristics (potentially indicating alikelihood of ESA condition) persist for a predetermined time period.

The ESA categorization routine of the analyte sensor calibrationmanagement algorithm, in one aspect, may be configured to categorize thesensor signal characteristics into three levels that are based on theconfidence in the existence of ESA condition for the sensor. The routinemay be configured to assess the sensor signal by looking at themagnitude of the raw sensor signal (Sr), as well as the sensitivity ofthe sensor signal obtained from a reference glucose measurement, forwhich both magnitude (Si) and variation (dSi) from previous referencemeasurements are considered. Thresholds for each signal measurement (Sr,Si and dSi), assigned for each of the three algorithm categorizationlevels (0, 1 or 2), may be checked to assign the sensitivity to one ofthe three ESA categories.

The three categories indicate the confidence level or the likelihoodthat ESA condition is present for the analyte sensor. For example, NoESA (level 0) indicates that there is no likelihood that ESA conditionis present for the sensor. Possible ESA (level 1) indicates that theremay be a possibility of ESA condition present for the sensor at thiscalibration event. Further, Likely ESA (level 2) indicates that it islikely there is ESA condition present for the sensor at the currentcalibration event. The checks for these measurements are performed ateach calibration measurement, for example, when the user performs afingerstick test to provide the reference blood glucose measurement,resulting in the appropriate categorization for each calibration event.Since the probability of the ESA signal characteristic varies withelapsed time from the initiation of sensor wear, the thresholds for theESA categorization routine may vary over time. The thresholds may alsovary based on the outcome of previous calibration measurements for anygiven sensor, since the probability that a given calibration will resultin a detection of ESA increases when a signal perturbation has beenpreviously observed for the sensor.

The ESA management routine of the sensor calibration managementalgorithm in one aspect of the present disclosure has three outcomesthat are based on the level of confidence in the presence of ESAcondition for the sensor. For calibrations that are categorized ashaving No ESA (level 0), it is not likely that an ESA event will resultin inaccurate results, and therefore, the sensor data corresponding tothe monitored analyte level are determined and reported based on thesensitivity obtained from the calibration event.

For calibrations that are categorized as Possible ESA (level 1), thesensitivity estimate may likely be valid for a limited time period, andtherefore, the sensor data corresponding to the monitored analyte levelmay be determined and reported to the user based on the sensitivityobtained from the calibration event on a probationary basis (for apredetermined time period such as, for example, two hours or any othersuitable probationary time period), after which the user may be promptedto perform another calibration to confirm the continued validity of thesensitivity obtained from calibration.

For calibrations categorized as Likely ESA (level 2), it is highlylikely that the sensor data corresponding to the monitored analyte levelwill include substantial attenuation or error, and therefore, thereporting or output of the sensor data is suspended for a predeterminedwait period during which the sensor signal is allowed to recover (forexample, from the temporary attenuation). At the end of thepredetermined wait time period, the user may be requested to performanother fingerstick test to perform another calibration to verify thatESA condition is no longer present or that it is insignificant.

In this manner, in accordance with various embodiments of the presentdisclosure, analyte sensor calibration management is provided whicheffectively processes the analyte sensor signals to maximize theaccurate reporting of the monitored analyte level while minimizing thepotential for providing false or erroneous readings from the sensorduring the occurrence of signal attenuation events.

In one aspect of the present disclosure, the routines and algorithmsdescribed herein may be incorporated in the receiver unit 104/106, thedata processing unit 102, or the data processing terminal/infusionsection 105 of the analyte monitoring system 100 (FIG. 1). Morespecifically, in accordance with the embodiments of the presentdisclosure, there may be provided one or more signal detectorsconfigured to perform some, shared or all of the routines describedherein to management sensor calibration for the ESA detection, the ESAcategorization, and the ESA management, by for example, one or moreprocessors, state machines and the like which may include integratedcircuits, application specific integrated circuits (ASIC), and/orcombination of hardware and software components including memory devicessuch as random access memory (RAM), read only memory (ROM), solid statedrives, and the like.

More specifically, in one embodiment, a plurality of signal detectorsmay be used to implement the calibration management routine describedherein. A first signal detector may be configured for detection of ESAstate based on blood glucose measurements or other reference informationand the analyte sensor data from the sensor analyte monitoring system.The outcome of a first signal detector may be configured to determinewhether the monitored sensor signal from the analyte monitoring systemis in ESA condition.

A second signal detector may be configured to monitor the analytemonitoring system sampled data (for example, one minute data, or anysuitable sampling rate). In one aspect, a second signal detector may beconfigured to instruct the analyte monitoring system to prompt the userto enter an immediate or scheduled blood glucose measurement (forexample, based on a fingerstick test using a blood glucose meter) toconfirm whether an ESA condition exists, and to be used in conjunctionwith the first signal detector—i.e., the detection of ESA state of theanalyte monitoring system based on the reference blood glucosemeasurements.

In one aspect, the first and second signal detectors are configured togenerate one of a plurality, e.g., three, ESA levels—level 0: no ESA,level 1: possible ESA, and level 2: likely ESA. As discussed above, inone aspect, the level 1 condition associated with possible ESA state ofthe sensor may be characterized as no significant signal attenuation butbased on the detected or monitored conditions associated with thesensor, a verification of the potential ESA condition is desired ornecessary within a predetermined period, such as, two hours (or anyother suitable time period).

First Signal Detector and ESA Categorization Module

The fingerstick test (or reference blood glucose measurement)-based ESAdetector (ESA_FS) operates when a calibration attempt passes a datacondition verification routine during the active ESA detection phase.More specifically, the ESA_FS detector starts its activity at the firstbaseline calibration (for example, at about one hour or less from thetime of sensor insertion). It remains active during the initial phase ofthe sensor life (for example, approximately the first 24 hours frominitial insertion) when the likelihood of ESA condition is greatest.

In one embodiment, the first signal detector takes the role of “ESACategorization” module 620 (FIG. 6) during active ESA conditiondetection phase. In addition, if other signal detectors do not suspectESA condition, but an eligible fingerstick blood glucose measurement ismade during the active ESA condition detection phase, the first signaldetector also takes the role of “ESA Detection” module 610.

The ESA_FS detector uses two tests, one relative and one absolute,either of which can detect signal attenuation levels (ESA_FS level)based on any reference blood glucose measurement within the active ESAdetection phase. The higher of the two levels may be chosen if they arenot the same for the two tests. More specifically, in one embodiment,the relative test compares the value of the latest immediate sensitivitybased on the latest fingerstick blood glucose test, Si(k), to the valuesof the previous immediate sensitivity, Si(k−1), and the most recentimmediate sensitivity used to calculate the composite sensitivity,Si(m). The values Si(k), Si(k−1), and Si(m) are selected such thatcalibration post condition verifications pass at those instances (attime index k, k−1, and m). In one aspect, manual calibrations aresubject to the tests performed by the ESA_FS detector, but the resultingimmediate sensitivities may not be used as previous values.

Based on the relative test, two ratios are formed, S_(i)(k)/S_(i)(k−1),and S_(i)(k)/S_(i)(m). The two threshold values of ESA_FS levels areassigned using these ratios as follows:

(1) ESA_FS level 2 (likely ESA condition) if:

S _(i)(k)/S _(i)(k−1)<K _(lo_Rel_ESA_FS[2]), OR S _(i)(k)/S _(i)(m)<K_(lo_Rel_ESA_FS_Cal[2]),

(2) ESA_FS level 1 (possible ESA condition) if NOT ESA_FS level 2 AND:

S _(i)(k)/S _(i)(k−1)<K _(lo_Rel_ESA_FS[1]), OR S _(i)(k)/S _(i)(m)<K_(lo_Rel_ESA_FS_Cal[1]),

where K_(lo_Rel_ESA_FS[2]) is less than or equal toK_(lo_Rel_ESA_FS[1]), and further, K_(lo_Rel_ESA_FS_Cal[2]) is less thanor equal to K_(lo_Rel_ESA_FS_Cal[1]), and further, where each of theseparameters may be predetermined values (for example, set at 0.5 or 0.75or other suitable value) programmed or programmable in the receiver unit104/106 (FIG. 1) of the analyte monitoring system, for example.

Otherwise, the relative test of ESA_FS generates a level 0 outputindicative of absence of ESA condition.

In accordance with aspects of the present disclosure, the absolute testcompares the sensitivity level S_(i)(k) to sensitivity thresholds scaledto the analyte sensor nominal sensitivity S_(nom). As in the relativetest, S_(i)(k) may be chosen such that it passes calibration postcondition verifications. ESA_FS levels are assigned as follows:

ESA_FS level 2 (likely ESA condition) if:S_(i)(k)/S_(nom)<K_(min_Abs_ESA_FS[2])

ESA_FS level 1 (possible ESA condition) if NOT ESA_FS level 2 AND:

S _(i)(k)/S _(nom) <K _(min_Abs_ESA_FS[1])

where <K_(min_Abs_ESA_FS[2]) is less than equal toK_(min_Abs_ESA_FS[1]), and further, each of these two parameters may bepredetermined or programmed.

Otherwise, the absolute test of ESA_FS generates a level 0 output(indicating no detected ESA condition).

The threshold values for the relative and absolute tests above may bevalid when the likelihood of ESA condition is the greatest. When the ESAdetectors remain active beyond that time up to an absolute latest timebeyond which the ESA detection will be ignored by the system, thelikelihood of ESA may be assumed to be correlated to the elapsed timesince sensor insertion, and that different likelihoods allow fordifferent tradeoffs between maximizing ESA detection and minimizing thenumber of calibration requests.

Second Signal Detector

The second signal detector in the analyte monitoring system is based oninferring ESA condition from the analyte sensor signal characteristics.One example of a signal characteristic is the detection of low glucosevalues. When this detector reports a nonzero ESA level (for example,presence of signal attenuation (ESA)), there are two possibilities:either the system is in ESA, or the user is in (or near) hypoglycemia.

In one embodiment, the second signal detector may be configured toinclude the functions of the “ESA Detection” module 610 (FIG. 6), and isnot used solely to categorize the detected ESA condition for the “ESAManagement” module 630 of the overall system. When the second signaldetector produces a nonzero output, a reference blood glucosemeasurement is expected in a manner determined by the “ESA Management”module 630 of the overall system.

To minimize the effect of noise, a predefined number of the most recentunfiltered glucose samples from the analyte sensor, G_(CAL), areaveraged to derive at the glucose value G_(ESA_CGM).

The detector reports one of three possible ESA levels based on theglucose value G_(ESA_CGM):

ESA level 2 (likely ESA condition) if: G_(ESA_CGM)<G_(min_ESA_CGM[2])

ESA level 1 (possible ESA condition) if NOT ESA_FS level 2 AND:

G _(ESA_CGM) <G _(min_ESA_CGM[1])

where G_(min_ESA_CGM[2]) is less than or equal to G_(min_ESA_CGM[1]),and further, correspond to predetermined values or parameters programmedinto the system.

Otherwise, the absolute test of ESA generates a level 0 outputindicating no detected ESA condition. Furthermore, if all of the mostrecent predefined number of unfiltered glucose sample G_(CAL) is notavailable, the second signal detector may be configured to report a zerolevel.

ESA Event Manager

In one embodiment, different roles of the first signal detector and thecoexistence of the second signal detector may be managed by the “ESAManagement” module 630 (FIG. 6). The ESA management may be influenced bythe sensitivity and specificity of each detector, the history of past orprior calibration events and reference blood glucose measurement timing,the scheduled calibration events in the near future, and other aspectsincluding usability.

In the case where the sensor is in the level 0 condition indicatingabsence of ESA condition, the second signal detector may be configuredto begin to operate after the second baseline calibration (that is, thesecond scheduled calibration time period for the analyte sensor) whichmay be a floating calibration event (measured from when the no ESAcondition is determined) scheduled following the first absolutecalibration (measured from the initial sensor insertion event) andthereby reporting measured glucose levels to the user. In one aspect,the display or output of the measured glucose levels may be suspended ata predetermined time associated with the earliest allowable terminationof the signal detectors in the system.

In order to avoid closely spaced fingerstick blood glucose measurements,in one aspect, the output from the second signal detector may be ignoredwhen either less than a predefined idle time period has elapsed after asuccessful baseline calibration where asynchronous stability request isnot allowed (for example, 30 minutes) after any calibration attempt, orwhen less than a predefined idle time period has elapsed prior to thenext scheduled baseline calibration where asynchronous stability requestis not allowed (for example, 30 minutes) before any scheduledcalibration attempt.

In one aspect, during active ESA detection phase, the first signaldetector is used to determine whether ESA condition is present orabsent. In one embodiment, it is assumed that ESA condition is absent atthe sensor start—that is, when the sensor is initially inserted. Thetransition, behavior, and retention of the states in one aspect aredescribed below. For example, in one aspect, transition into adetermination that ESA condition is present occurs when the latestESA_FS level is determined to be greater than the largest allowableoutput level from the first signal detector of prior measurements thatis considered as an indication of being free from early signalattenuation. For example, in the case where level 0 and level 1 areconsidered not sufficiently stringent for attenuation mitigation, in oneaspect of the present disclosure, only level 2 may be configured totrigger the transition to a state where it is determined that ESAcondition is present.

When the analyte monitoring system determines that the sensor is in ESAcondition, in one aspect, the receiver unit 104/106 (FIG. 1) may beconfigured to disable the output or display of the measured or detectedglucose level. Moreover, the receiver unit 104/106 may be configured tomaintain the disabled (or suspended or deactivated) output/display for apredefined idle time period after the presence of ESA condition has beenconfirmed by the reference blood glucose measurement before the user isprompted for another confirmation (for example, by requesting anotherfingerstick test) before transitioning to the state with confirmed noESA condition.

Furthermore, in yet another aspect, receiver unit 104/106 may beconfigured to not request a stability calibration verification whilesensor is in ESA condition. However, any user-motivated orself-initiated fingerstick blood glucose measurement may be used, ifconfirmed, to transition into a state where ESA condition is absent.Also, when the sensor is deemed to be in the confirmed no ESA condition,the second signal detector shows a level 0 (reflecting a no ESAcondition), and signal precondition verification passes, the receiverunit 104/106 (FIG. 1) of the analyte monitoring system may be configuredto request a reference blood glucose measurement to confirm that theabsence of ESA condition is complete and/or to initiate calibration.

In one aspect, transition into a state associated with absence of ESAcondition occurs when a new fingerstick blood glucose measurement showsan ESA_FS level (for example, the output of the first signal detectordiscussed above) that is less than or equal to the largest allowableoutput level from the first signal detector of prior measurements thatis considered as an indication of being free from early signalattenuation. A successful calibration is required for glucose results tobe reported or displayed, for example.

When it is determined that ESA condition is absent, the sensor signals,in one aspect may be further processed to determine stability andpossible errors. For example, in one aspect, when a level 2 output(i.e., likely ESA condition) from the second signal detector occurs forthe first time, an immediate request for a stability calibration may begenerated. After the first occurrence of level 2 output from the secondsignal detector, the analyte sensor signals are checked at the timeintervals (for example, approximately 1 to 2 hours, or other suitabletime interval) since the last reference blood glucose measurement withstability verification routine before another measurement is requested,after the most recent successful calibration. Further, a nonzero level(i.e., a level 1 or level 2—possible or likely ESA condition) triggers astability calibration request. Also, in one aspect, if a previous ESA_FSlevel is greater than 0, a reference blood glucose measurement isrequested at a time interval since the last blood glucose measurement,and ESA_FS is determined using the new reference measurement.

Referring now to the Figures, FIG. 6 is a flowchart illustrating anoverall analyte sensor calibration management in accordance with oneembodiment of the present disclosure. As shown, analyte sensorcalibration management system in accordance with one aspect of thepresent disclosure includes an ESA detection module 610, and ESAcategorization module 620, and an ESA management module 630. Asdiscussed above, the ESA detection module 610 is configured to detectthe occurrence of an early signal attenuation event during the initialtime period following the analyte sensor insertion or wear, for example,the first 24 hour period measured from the initial sensor insertion.

When signal attenuation associated with an analyte sensor is detected,the ESA categorization module in one embodiment is configured toproperly categorize the detected signal attenuation condition.Thereafter, depending upon the type of ESA condition detected—forexample, no ESA condition detection, likely ESA condition detection, orpossible ESA condition detection, the ESA management module 630 isconfigured to initiate one or more processes to confirm the detected andcategorized signal attenuation condition. And further, to performadditional processing to effectively manage the calibration algorithmassociated with the analyte sensor operation such that maximumreportable data yield may be attained, providing improved usability ofthe analyte sensor for continuously or intermittently monitoring andoutputting monitored analyte level such as the fluctuation in theglucose level of a patient or a user.

FIG. 7 is a flowchart illustrating early signal attenuation (ESA)detection routine of FIG. 6 in accordance with one aspect of the presentdisclosure. Referring to FIG. 7, the ESA detection routine executed bythe ESA detection module 610 (FIG. 6), for example, is described. Morespecifically, for each monitored signal from the analyte sensor (such asfor each one minute data from the analyte sensor), a new timestep isinitiated (701), and it is determined whether ESA detector should be orhas started (702). If it is determined that the ESA detector has not orshould not be started, then the routine waits for the next time step(714) based on the next signal received from the sensor (for example,the subsequent one minute signal received from the analyte sensor).

Referring to FIG. 7, if it is determined that ESA detector should or didstart (702), then it is determined whether it should be terminated(703). If it is determined that the ESA detector should be terminated(703), then the routine ends (704). However, if it is determined thatthe ESA detector should not terminate (703), then it is determinedwhether a pending reference blood glucose measurement request timer hasbeen activated (705). If it is determined that the pending referenceblood glucose measurement request timer has been activated (705), thenin one embodiment, a reference blood glucose measurement request isgenerated and output to the user with a nonzero grace period (706).Thereafter, the ESA detector is suspended and the system awaits for therequested reference blood glucose measurement (708).

On the other hand, if it is determined that the pending reference bloodglucose measurement request timer is not activated (705), then analytesensor signal information as well as other relevant information isretrieved or obtained (707). That is, for example, the sensor rawcurrent signal, the associated temperature information, sensor countervoltage data, for example, are obtained, in addition to other relevantinformation such as, for example, the sensor code sensitivity, immediatesensitivity, time duration elapsed since the sensor insertion, and timeelapsed since the prior sensor calibration event, for example. Withinthe scope of the present disclosure, other relevant data related to theoperation and characteristics of the analyte sensor may be obtained.

Referring still to FIG. 7, thereafter, the probability or ESA conditionpresence is determined (709), the result of which is compared to one ormore threshold values to determine whether high ESA conditionprobability exists (710). If it is determined that high ESA conditionprobability exists, then reference blood glucose measurement data isrequested with a nonzero grace period (711), and the ESA detectionroutine is suspended to await for the requested reference blood glucosemeasurement data. On the other hand, if it is determined that high ESAcondition probability does not exist (710), then it is determinedwhether medium ESA condition probability exists (712). If it isdetermined that medium ESA condition probability does not exist, thenthe routine proceeds to wait for the next sensor data (714). On theother hand, if it is determined that medium ESA condition probabilityexists (712), then a pending reference blood glucose measurement timeris set to activate at a predetermined relative time in the future,unless a successful calibration event is detected prior to theexpiration of the activated timer (713).

In the manner described above, in one embodiment of the presentdisclosure, the ESA detection module 610 (FIG. 6) may be configured todetect attenuation in analyte sensor signal during the initial timeperiod from the sensor insertion.

Referring back to the Figures, FIG. 8 is a flowchart illustrating earlysignal attenuation (ESA) categorization routine of FIG. 6 in accordancewith one aspect of the present disclosure. As described in detail above,upon detection of a signal attenuation occurrence associated with ananalyte sensor, the detected attenuation is categorized by, for example,the ESA categorization module (620). More specifically, referring now toFIG. 8, for each new timestep associated with the detection of the oneminute sensor signal from the analyte sensor, for example (810), it isdetermined whether ESA detector is active (820). If it is determinedthat the ESA detector is not active (or the ESA routine is not activatedor initiated), then the ESA categorization routine terminates (821).

On the other hand, if it is determined that the ESA detector is active(820), then it is determined whether a new reference blood glucosemeasurement is available (830). If the reference blood glucosemeasurement is not available, then the routine terminates and waits forthe next analyte sensor signal (860). If it is determined, however, thatthe reference blood glucose measurement is available (830), then analytesensor related information is retrieved and/or collected (840). In oneembodiment, analyte sensor related information may include, for example,sensor signal history, previous reference blood glucose measurementvalues, calibration time period, and the like. Thereafter, the detectedsignal attenuation is categorized into one of three categories—level 0,level 1, and level 2 (850), corresponding to no ESA condition, possibleESA condition, and likely ESA condition, respectively and as discussedin detail above. In one embodiment, after categorization, the routineproceeds to the ESA management module (630) (FIG. 6) and also, repeatsthe same categorization procedure for the next received sensor signal(860).

Referring back, as discussed, after performing ESA conditioncategorization (620) (FIG. 6), in one aspect, the ESA conditionmanagement routine is initiated (630). More specifically, FIG. 9 is aflowchart illustrating early signal attenuation (ESA) management routineof FIG. 6 in accordance with one aspect of the present disclosure. Asshown, for each analyte sensor signal received or detected (901), it isfirst determined whether the ESA detector is active (902). If it isdetermined that the ESA detector is not active, then the ESA managementroutine terminates (903).

On the other hand, if it is determined that the ESA detector is active,then it is determined whether a grace period of an existing referenceblood glucose measurement request has expired (904). If it is determinedthat the grace period of the existing reference blood glucosemeasurement request has expired, then the display or reporting moduleassociated with the output of the analyte sensor data is disabled,suspended, deactivated or otherwise blanked such that no real timeglucose information is provided to the user (910). If it is determinedhowever, that the grace period of the existing reference blood glucosemeasurement request has not expired, then the ESA categorization moduleoutput from the ESA categorization module (620) is retrieved (905).

Referring again to FIG. 9, it is thereafter determined whether the ESAcategorization result or output exists (906). If not, then the output orreporting of the real time glucose information proceeds and the user isprovided with the glucose level data (914), and thereafter waits toreceive the next analyte signal associated with the next timestep (918).On the other hand, if the ESA categorization result exists (906), thenit is determined whether the ESA categorization is associated with thecurrent analyte signal (associated with the current timestep, forexample) (907). If it is not associated with the current analyte signal,then the routine proceeds to displaying or outputting the monitoredanalyte level to the user (914), and waits to receive the next analytesignal associated with the next timestep (918).

However, if it is determined that the ESA categorization is associatedwith the current timestep (907), then it is determined whether the ESAcondition categorization is associated with level 2 category indicatinga likely ESA condition for the sensor (908). If it is determined thatthe ESA condition categorization is associated with level 2 category,then a timer (T_Confirm timer) is started (909) and the reporting oroutput of the glucose data is disabled (910). If it is determinedhowever, that the ESA condition category is not associated with level 2(908), then it is determined whether the categorized ESA condition islevel 1 (911). If it is determined to be level 1 indicating a possibleESA condition, then a request for a blood glucose measurement isscheduled for a predetermined time period (T_Cal_U) with a nonzero graceperiod (912), and the real time glucose information is displayed oroutput to the user (914).

Referring back to FIG. 9, if it is determined that the ESA condition isnot associated with a level 1 category (911), then the calibration forthe analyte sensor is updated (913), and the monitored glucose level isdisplayed or output to the user (914), and the routine waits to receivethe next analyte sensor signal (918). Referring still back to FIG. 9,after the display or output of the glucose value is disabled or blanked(910), it is determined whether the T_Confirm timer was started and thetimer expired (915). If it has not expired, the routine waits to receivethe next analyte signal (918). If, however, it is determined that thetimer (T_Confirm) has lapsed (915), then it is determined whether thecharacteristics of the sensor is suitable, for example, for calibration(916). If it is determined that the sensor condition is not suitable(916), then the routine waits to receive the next analyte sensor signal(918). On the other hand, if it is determined that the sensor conditionis stable (916), then a reference blood glucose measurement is requestedwith a zero grace period (917).

In the manner described above, in accordance with the variousembodiments of the present disclosure, a method, apparatus and systemfor providing effective analyte sensor calibration management isdescribed that monitors the early attenuation of sensor signals andprocesses the monitored signals to maximize the sensor data yield byproviding as much of the useful and accurate monitored glucose levelinformation to the user.

Results from Preliminary Studies

A preliminary study, was conducted with 48 sensor insertions in normal(N=10), T1DM (N=1) and T2DM (N=2) subjects using finger stick glucosemeasurements as a reference. Little deterioration of the results wasobserved when comparing the mean absolute relative difference (MARD) forthe first 10 hours compared to the remaining 10 to 24 hours of day oneof sensor use: 13.8% (12.8-14.9 95% CI) versus 12.6% (11.6-13.6 95% CI)respectively. During the first ten hours 7.5 hours±2.2 hours(average±SD) of glucose data would be available to the usersubstantially maximizing available data yield providing reportableglucose information shortly after the sensor insertion.

A second preliminary study included evaluation of the performance of thesystem described above which included two locations each with 47subjects (aged 19-66) who wore 2 sensors (abdomen/arm). Continuousglucose readings were collected at one minute intervals from 1 hourafter sensor insertion. Venous blood glucose measurements were obtainedusing a standard laboratory reference (YSI 2300) every 15 minutes for 26hours across two in-clinic visits during the 5 day sensor wear.Capillary BG measurements were taken by each subject (on average 20 perday) on a separate blood glucose meter.

The mean and median absolute relative difference between the sensorsystem and YSI was 14.5% and 10.7% respectively. Moreover, continuousGlucose-Error Grid Analysis combining rate and point information gave93.9% accurate readings and an additional 3.2% benign errors.

Traditional Clarke Error Grid (CEG) Zone A performance was 77.1%(6229/8084). This included periods of hypoglycemia and high rates ofchange of blood glucose during IV insulin challenges. When the rate ofchange of blood glucose was within ±1 mg/dL/min, the Zone A performancewas 82.0% (4672/5699). Performance remained constant over all five days,with 80.7% of data in Zone A on day 1 and 74.1% in Zone A on day 5(p=0.4503). Furthermore, Clarke Error Grid Zone A performance comparedto capillary blood glucose measurement was 81.2% (3337/4108).

Hypoglycemic events at 70 mg/dL (n=119) were detected by threshold orprojected alarm (30 minute setting) 91.6% of the time. Hyperglycemicevents at 240 mg/dL (n=144) were detected by threshold or projectedalarm 97.2% of the time. The threshold or projected alarm false alarmrate was 25.2% at 70 mg/dL and 21.2% at 240 mg/dL.

Based on the foregoing, the results from the second preliminary studydemonstrate good performance of the FreeStyle Navigator® ContinuousGlucose Monitoring System with data displayed from approximately onehour after sensor insertion over five days of sensor wear.

In the manner described above, in accordance with the variousembodiments of the present disclosure, the analyte sensor calibrationmanagement minimizes the presentation of erroneous analyte sensorresults due to ESA conditions, while maximizing reportable analytesensor data for sensors that do not exhibit the ESA signalcharacteristic. Accordingly, in aspects of the present disclosure, thecalibration management algorithm applies to any subcutaneouslypositioned analyte sensor which may exhibit ESA signal characteristics,and enables the management of calibration during periods when theanalyte sensor sensitivity may deviate from the actual sensorsensitivity.

Accordingly, a method in one aspect includes monitoring for a signallevel below a predetermined threshold associated with analyte level froman analyte sensor during a predefined time period, and reporting analytelevel associated with the analyte sensor when the signal level monitoredis not detected during the predefined time period.

The predefined time period may include less than approximately one hour.

In another aspect, the method may include receiving a blood glucosemeasurement, and calibrating the analyte sensor based on the receivedblood glucose measurement.

Further, the predetermined threshold may be associated with one or moreof an impending hypoglycemic state, or a predefined signal attenuationlevel.

Also, reporting the analyte level may include one or more of storing theanalyte level, confirming the analyte level, or outputting the analytelevel.

The various processes described above including the processes performedby the data processing unit 102, receiver unit 104/106 or the dataprocessing terminal/infusion section 105 (FIG. 1) in the softwareapplication execution environment in the analyte monitoring system 100including the processes and routines described in conjunction with FIGS.6-9, may be embodied as computer programs developed using an objectoriented language that allows the modeling of complex systems withmodular objects to create abstractions that are representative of realworld, physical objects and their interrelationships. The softwarerequired to carry out the inventive process, which may be stored in thememory or storage device (not shown) of the data processing unit 102,receiver unit 104/106 or the data processing terminal/infusion section105, may be developed by a person of ordinary skill in the art and mayinclude one or more computer program products.

One embodiment of the present disclosure may include positioning ananalyte sensor in fluid contact with an analyte, detecting anattenuation in a signal from an analyte sensor after positioning duringa predetermined time period, categorizing the detected attenuation inthe analyte sensor signal based, at least in part, on one or morecharacteristics of the signal, and performing signal processing togenerate a reportable data associated with the detected analyte sensorsignal during the predetermined time period.

The signal from the analyte sensor may be associated with a monitoredanalyte level.

The detected attenuation in the signal from the analyte sensor may beassociated with an early signal attenuation condition.

The predetermined time period may not exceed approximately 24 hours.

Categorizing the detected analyte sensor signal attenuation may be basedat least in part on a predetermined plurality of signal attenuationconditions.

In one aspect, the plurality of signal attenuation conditions mayinclude a reportable signal condition, a conditional reportable signalcondition, and an unreportable signal condition.

Another aspect may include outputting data associated with the monitoredanalyte level based on the detected analyte sensor signal when thedetected analyte sensor signal attenuation includes a reportable signalcondition or a conditional reportable signal condition.

Outputting data associated with the monitored analyte level may includeoutputting data for a preset time period when the detected analytesensor signal attenuation includes the conditional reportable signalcondition.

The preset time period may not exceed approximately two hours.

One aspect may include requesting a reference blood glucose measurementduring the preset time period.

Another aspect may include calibrating the analyte sensor signal basedat least in part on the reference blood glucose measurement receivedduring the preset time period.

Yet another aspect may include disabling outputting of the dataassociated with the monitored analyte level after the preset time periodhas elapsed.

Another embodiment, wherein performing signal processing may includerequesting a reference data, and determining a sensitivity valueassociated with the analyte sensor based on the reference data.

The reference data may include an in vitro blood glucose measurementdata.

One aspect may include calibrating the analyte sensor based at least inpart on the determined sensitivity value.

A further embodiment of the present disclosure includes monitoring for asignal level below a predetermined threshold associated with analytelevel from an analyte sensor during a predefined time period, andreporting analyte level associated with the analyte sensor when thesignal level monitored is not detected during the predefined timeperiod.

The predefined time period may be less than approximately one hour.

Another aspect may include receiving a blood glucose measurement, andcalibrating the analyte sensor based on the received blood glucosemeasurement.

The predetermined threshold may be associated with one or more of animpending hypoglycemic state, or a predefined signal attenuation level.

Reporting the analyte level may include one or more of storing theanalyte level, confirming the analyte level, or outputting the analytelevel.

Yet still another aspect of the present disclosure includes inserting atleast a portion of a glucose sensor beneath a skin surface of anindividual, analyzing glucose-related signal from the sensor todetermine sensor stability, and reporting glucose related information tothe individual only when it is determined that the sensor is stable,wherein the glucose related information is not reported prior todetermination that the sensor is stable.

Sensor stability may be determined using reference data.

Reference data may comprise sampling blood of the individual.

Reference data may be obtained from a glucose test strip.

One aspect may include analyzing the sensor signal to determine whetherthere exists a decrease in sensor signal.

The analyte sensor may report the glucose related information in aboutone hour following the insertion.

An apparatus in accordance with still another aspect may include a datacommunication interface, one or more processors operatively coupled tothe data communication interface, and a memory for storing instructionswhich, when executed by the one or more processors, causes the one ormore processors to position an analyte sensor in fluid contact with ananalyte, detect an attenuation in a signal from an analyte sensor afterpositioning during a predetermined time period, categorize the detectedattenuation in the analyte sensor signal based, at least in part, on oneor more characteristics of the signal, and perform signal processing togenerate a reportable data associated with the detected analyte sensorsignal during the predetermined time period.

The signal from the analyte sensor may be associated with a monitoredanalyte level.

The detected attenuation in the signal from the analyte sensor may beassociated with an early signal attenuation condition.

The predetermined time period may not exceed approximately 24 hours.

In one aspect, the memory for storing instructions which, when executedby the one or more processors, may cause the one or more processors tocategorize the detected analyte sensor signal attenuation based at leastin part on a predetermined plurality of signal attenuation conditions.

The plurality of signal attenuation conditions may include a reportablesignal condition, a conditional reportable signal condition, and anunreportable signal condition.

In another aspect, the memory for storing instructions which, whenexecuted by the one or more processors, may cause the one or moreprocessors to output data associated with the monitored analyte levelbased on the detected analyte sensor signal when the detected analytesensor signal attenuation includes a reportable signal condition or aconditional reportable signal condition.

In yet another aspect, the memory for storing instructions which, whenexecuted by the one or more processors, may cause the one or moreprocessors to output data for a preset time period when the detectedanalyte sensor signal attenuation includes the conditional reportablesignal condition.

Furthermore, the preset time period may not exceed approximately twohours.

Moreover, the memory for storing instructions which, when executed bythe one or more processors, may cause the one or more processors torequest a reference blood glucose measurement during the preset timeperiod.

Further, the memory for storing instructions which, when executed by theone or more processors, may cause the one or more processors tocalibrate the analyte sensor signal based at least in part on thereference blood glucose measurement received during the preset timeperiod.

Moreover, the memory for storing instructions which, when executed bythe one or more processors, may cause the one or more processors todisable the outputting of the data associated with the monitored analytelevel after the preset time period has elapsed.

In another aspect, the memory for storing instructions which, whenexecuted by the one or more processors, may cause the one or moreprocessors to request a reference data, and determine a sensitivityvalue associated with the analyte sensor based on the reference data.

Reference data may include an in vitro blood glucose measurement data.

Further, the memory for storing instructions which, when executed by theone or more processors, may cause the one or more processors tocalibrate the analyte sensor based at least in part on the determinedsensitivity value.

Moreover, in still another aspect, there is provided one or more storagedevices having processor readable code embodied thereon, said processorreadable code for programming one or more processors to estimate ananalyte level may comprise, positioning an analyte sensor in fluidcontact with an analyte, detecting an attenuation in a signal from ananalyte sensor after positioning during a predetermined time period,categorizing the detected attenuation in the analyte sensor signalbased, at least in part, on one or more characteristics of the signal,and performing signal processing to generate a reportable dataassociated with the detected analyte sensor signal during thepredetermined time period.

Various other modifications and alterations in the structure and methodof operation of this disclosure will be apparent to those skilled in theart without departing from the scope and spirit of the embodiments ofthe present disclosure. Although the present disclosure has beendescribed in connection with particular embodiments, it should beunderstood that the present disclosure as claimed should not be undulylimited to such particular embodiments. It is intended that thefollowing claims define the scope of the present disclosure and thatstructures and methods within the scope of these claims and theirequivalents be covered thereby.

1. (canceled)
 2. A system, comprising: an analyte sensor; sensorelectronics coupled to the analyte sensor to receive signals generatedby the analyte sensor and to generate data corresponding to an analytelevel; and a receiving device, comprising: a user interface; one or moreprocessors operatively coupled to the user interface; and a memorystoring instructions which, when executed by the one or more processors,causes the one or more processors to: receive the data corresponding tothe analyte level; operate a predetermined analyte detection routine toreport the data corresponding to the analyte level using the userinterface; determine a presence of an error condition; provide anotification on the user interface, the notification including a requestthat a user provide a blood analyte measurement; when a predeterminedperiod of time has elapsed after providing the notification, determinethat the user has not provided the blood analyte measurement; and inresponse to determining that the user has not provided the blood analytemeasurement, disable the user interface from reporting the datacorresponding to the analyte level.
 3. The system of claim 2, whereinone or more processors receive the data corresponding to the analytelevel according to at least a Bluetooth communication protocol.
 4. Thesystem of claim 3, wherein the one or more processors receive the datacorresponding to the analyte level in real-time, and determine thepresence of an error condition in real-time.
 5. The system of claim 2,wherein the receiving device comprises a test strip port to receive ananalyte test strip.
 6. The system of claim 2, wherein the one or moreprocessors determine the presence of the error condition by at leastevaluating one or more sensor-related characteristics of the datacorresponding to the analyte level, and comparing the one or moresensor-related characteristics to one or more predetermined attenuationevents.
 7. The system of claim 2, wherein the analyte sensor comprises aplurality of electrodes including a working electrode comprising ananalyte-responsive enzyme bonded to a polymer disposed on the workingelectrode.
 8. The system of claim 7, wherein the analyte-responsiveenzyme is chemically bonded to the polymer.
 9. The system of claim 7,wherein the working electrode further comprises a mediator.
 10. Thesystem of claim 2, wherein the analyte sensor comprises a plurality ofelectrodes including a working electrode comprising a mediator bonded toa polymer disposed on the working electrode.
 11. The system of claim 10,wherein the mediator is chemically bonded to the polymer.
 12. A device,comprising: a user interface; one or more processors operatively coupledto the user interface; and a memory storing instructions which, whenexecuted by the one or more processors, causes the one or moreprocessors to: receive data corresponding to an analyte level from asensor electronics coupled to an analyte sensor; operate a predeterminedanalyte detection routine to report the data corresponding to theanalyte level using the user interface; determine a presence of an errorcondition; provide a notification on the user interface, thenotification including a request that a user provide a blood analytemeasurement; when a predetermined period of time has elapsed afterproviding the notification, determine that the user has not provided theblood analyte measurement; and in response to determining that the userhas not provided the blood analyte measurement, disable the userinterface from reporting the data corresponding to the analyte level.13. The device of claim 12, wherein one or more processors receive thedata corresponding to the analyte level according to at least aBluetooth communication protocol.
 14. The device of claim 13, whereinthe one or more processors receive the data corresponding to the analytelevel in real-time, and determine the presence of an error condition inreal-time.
 15. The device of claim 12, further comprising a test stripport to receive an analyte test strip.
 16. The device of claim 12,wherein the one or more processors determine the presence of the errorcondition by at least evaluating one or more sensor-relatedcharacteristics of the data corresponding to the analyte level, andcomparing the one or more sensor-related characteristics to one or morepredetermined attenuation events.
 17. The device of claim 12, whereinthe analyte sensor comprises a plurality of electrodes including aworking electrode comprising an analyte-responsive enzyme bonded to apolymer disposed on the working electrode.
 18. The device of claim 17,wherein the analyte-responsive enzyme is chemically bonded to thepolymer.
 19. The device of claim 17, wherein the working electrodefurther comprises a mediator.
 20. The device of claim 12, wherein theanalyte sensor comprises a plurality of electrodes including a workingelectrode comprising a mediator bonded to a polymer disposed on theworking electrode.
 21. The device of claim 20, wherein the mediator ischemically bonded to the polymer.